Lung infections remain a frequent and serious complication in persons infected with HIV-1, although the underlying mechanisms remain incompletely understood. Recognizing the important role of innate immunity in host defense recognition of pathogens and effector cell function, data from the first 5 years of this research project identified several critical deficiencies in lung innate host defense function in the context of HIV infection. Focusing on the alveolar macrophage (AM) mannose receptor as a prototypic receptor of innate immunity, data from this scientific project identify for the first time the molecular mechanism for mannose receptor-mediated phagocytosis and the independent regulation of critical host defense cell signaling pathways, whereas these signal transduction pathways are significantly altered in AM from HIV-infected persons. Furthermore, the abnormalities are specific (rather than a global disturbance of AM function), often involving or targeting critical components of AM innate response. Furthermore, the abnormalities in AM innate immune function are evident even in persons with clinical response to HAART and are independent of the extent of lung HIV expression. These data support the central hypothesis that HIV infection impairs specific critical AM innate immune receptor-mediated signal transduction pathways, which alter intrinsic AM function and contribute to the pathogenesis of Jung infections. This proposal seeks to define the influence of HIV-1 on specific AM pathways regulated by opsonin-independent recognition of opportunistic pathogens such as Pneumocystis with the following specific aims: #1) identify the molecular events that define mannose receptor-mediated phagocytosis of unopsonized opportunistic pathogens by AM from healthy individuals;#2) investigate specific host defense signal transduction pathways activated by mannose receptor-mediated recognition of opportunistic pathogens in AM from healthy individuals.;#3) investigate the mechanism of HIV-mediated alteration of mannose receptor expression, regulation, and function, examining alveolar macrophages from asymptomatic HIV+ persons at high and low clinical risk for lung infections, and alveolar macrophages from healthy individuals following in vitro HIV infection. Continued research on this project will identify novel therapeutic targets for the prevention and treatment of AIDS- related lung infections and improve the health of persons living with HIV.